Influenza vaccine and subsequent development of zoster

Abstract Background Herpes zoster (HZ), which is caused by reactivation of the latent varicella zoster virus, was not listed as a side effect of any vaccines until the introduction of coronavirus disease 2019 (COVID‐19) vaccine. This study used a nationwide population database to examine whether the HZ risk is increased after receiving the influenza vaccination. Methods This population‐based retrospective self‐controlled case series evaluated the association between influenza vaccine exposure and HZ risk. Data were collected from Taiwan's National Health Insurance Research Database between 2015 and 2017. Patients with HZ diagnosed within 6 months before and after receiving the influenza vaccination were included. After receiving the influenza vaccine, the first 15 and 30 days were defined as risk intervals, while the other periods were defined as control intervals. Poisson regression was used to compare the incidence rate ratio (IRR) for HZ during the risk interval vs. the control interval. Results In total, 13,728 patients were diagnosed with HZ before and after receiving the influenza vaccine. The IRR for days 1–15 was significantly higher (IRR = 1.11; 95% confidence interval [CI], 1.02–1.20), but insignificant for days 1–30 (IRR = 1.04; 95% CI, 0.98–1.10). In a subgroup analysis, the IRRs were significantly higher in participants, including 50–64 years old (1.16; 95% CI, 1.02–1.33), males (1.14; 95% CI, 1.01–1.28), and healthier individuals (i.e., no history of cancer or autoimmune diseases). Conclusions There was a slight increase in risk of HZ in people receiving influenza vaccine in the first 1–15 days after vaccination.

as control intervals. Poisson regression was used to compare the incidence rate ratio (IRR) for HZ during the risk interval vs. the control interval.
Conclusions: There was a slight increase in risk of HZ in people receiving influenza vaccine in the first 1-15 days after vaccination. (COVID- 19) pandemic. 3 There are, however, many reports of increased risk for HZ in people who received the COVID-19 vaccine, 4-6 especially mRNA-based vaccines. The exact mechanism whereby vaccines arouse VZV latency remains unclear. Some researchers believe that mRNA vaccines induce immune reconstitution, which has been reported in other types of vaccines, including adenovirus-or subunit-based vaccines. 7 The phenomenon described for COVID-19-associated HZ might be the same for conventional vaccines, e.g., influenza vaccines.
In this study, we used a nationwide population database to explore whether HZ risk increases after receiving the influenza vaccine.

| Background information
In Taiwan, a single-payer mandatory enrollment National Health Insurance (NHI) program was launched in 1995, which covered more than 99% of citizens of Taiwan. 8 The policy of free influenza vaccination for all people aged 65 years and older was implemented in 2001.
Other vaccination targets were gradually added, including medical staff, epidemic prevention workers, young children, patients with catastrophic illness, pregnant women, etc. In 2016, in order to protect the health of adults aged 50-64 years, this group was further included in the target of public-funded vaccines.

| Data source
This population-based study was a secondary data analysis using nationwide data from Taiwan's NHI research database (NHIRD). The data were released by the Health and Welfare Data Science Center, Ministry of Health and Welfare of Taiwan (HWDC, MOHW). The NHIRD of this study was covered during the 2015-2017 period and comprised the detailed information of beneficiaries enrolled in the NHI program, including clinical records on outpatient visits, hospitalizations, and prescriptions. According to the policies of Taiwan's NHI, medical claims are sent to the Bureau of NHI for cross-checking and validation to ensure the adequacy of diagnosis coding. Hospitals or clinicals found to have fraudulent coding, overcharging, or malpractice will be penalized or restrained of the treatment fees. Several validation studies have been performed to support the validity of diagnosis codes in the NHIRD. 8 Owing to the anonymity of the database, the requirement for informed consent was waived. This study was approved following an ethical review conducted by the Institutional Review Board of the Taichung Jen-Ai Hospital, Taiwan (Institutional Review Board No. 108-83).

| Study design and populations
We used a self-controlled case-series design to evaluate the association between influenza vaccination and HZ. The study population comprised patients who had been diagnosed with HZ within 6 months before and after receiving the influenza vaccine in 2016. After excluding patients (1) receiving influenza vaccine more than once (atypical way for influenza vaccine), (2) died within 6 months after receiving influenza vaccine, and (3) with missing value of confounding factors (age, sex, premium-based monthly salary, and urbanization level), we identified 13,728 patients who were enrolled as study subjects. A schematic algorithm detailing the study selection procedures is shown in Figure 1. Theoretically, if the HZ was not related to influenza vaccination, the incidence of HZ for our selection subjects would presumably be distributed equally across the entire observation period. The first 15 and 30 days after receiving the influenza vaccine were defined as risk intervals, and the other periods (6 months before and 5 months after receiving influenza vaccine) were defined as control intervals.

| Definition
To increase the accuracy of diagnosis, HZ was defined as having a primary diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]: 053.x, and Tenth Revision F I G U R E 1 Schematic of study design. "Herpes zoster (A)" represented the elderly who is diagnosed with herpes zoster at any time during the 15-day and 30-day risk interval (light-shaded areas) after influenza vaccination. "Herpes zoster (B)" represented the elderly who is diagnosed with herpes zoster during the control interval (dark-shaded areas). The study assessed the relative incidence of herpes zoster during the risk interval as compared to that during the control interval.
[ICD-10-CM]: B02.*) and concurrent use of related medications, including acyclovir (anatomic therapeutic chemical [ATC] code: J05AB01), famciclovir (ATC code: J05AB11), and valacyclovir (ATC code: J05AB09). The confounding factors adjusted for in this study included sex, age, premium-based monthly salary, urbanization level, the Charlson comorbidity index (CCI) score, 11 comorbid autoimmune diseases, and cancer. CCI scores were calculated using the diagnosis of outpatient or inpatient admission during the preceding 12 months prior to the vaccination date. In addition, we used the registry for catastrophic illness in the NHIRD to define whether subjects had comorbid autoimmune diseases or cancer.

| Statistical analysis
We used the Poisson regression to compute the incidence rate ratio (IRR) and 95% confidence interval (CI) for incident HZ during the risk interval compared to that in the control interval. The incidence of HZ per study subject during the observation period was accounted for in the model. We evaluated the risks of incident HZ during days 1-15, and 1-30 after receiving influenza vaccine, respectively. To test the robustness of our findings, we conducted two sensitivity analyses that limited the control interval to the post-exposure observation time (i.e., 5 months after receiving influenza vaccine) and limited the preexposure observation time to 6 months before receiving influenza vaccine. We also performed a stratified analysis in subgroups defined according to age (<50, 50-64, and ≥65 years), sex, CCI (score 0, 1, and ≥2), autoimmune disease, and cancer (present or absent). Statistical analysis was performed using the SAS software Version 9.4 (SAS Institute, Cary, NC, USA). A p-value <0.05 was considered statistically significant.

| DISCUSSION
By using a nationwide database, the current study revealed a marginal increase in HZ incidence within 1-15 days after receiving the influenza vaccine in the general population, particularly among individuals aged 50-64 years, as well as in those with few comorbidities, such as cancer and autoimmune diseases. This discrepancy in risk across different age groups and health status is novel and might be due to an increased risk for HZ in older people, which renders the effect of vaccination on HZ risk less apparent. In contrast, the incidence of HZ was significantly low in young people and those that were generally healthy. An increase in the number of HZ cases is therefore relatively easy to observe. Furthermore, although the IRR in patients with autoimmune diseases is not statistically significant, it might be due to the small number of cases contributing to its non-significance.
Previous studies have identified various factors which can lead to VZV reactivation, including aging, physical or emotional stress, immunosuppression, and some medication, such as Janus kinase inhibitors. 9,10 It is unlikely that the possible link between HZ and recent vaccination would cause physicians much concern, since HZ is common in day-to-day patient care, and supposedly more prevalent in elderly people who should receive influenza vaccines. However, studies using a large database should be able to reveal this unexpected increase in HZ with greater certainty. As an example, it is not surprising that HZ had not been considered a monitoring target during the initial international clinical trials of the COVID-19 vaccine. [11][12][13][14][15] The following massive vaccination supports that there is an increased risk of HZ following COVID-19 vaccination, which is unlikely to be coincident.
It is unclear whether influenza vaccines directly or indirectly reactivate VZV from its latent state. Immunization may impose significant psychological and physical stresses. Stress alone, however, is unlikely to be the sole cause. As discussed in the literature regarding COVID-19 vaccines, there is speculation that dysregulation of T cells and cellular immunity, 16 which are supposed to occur due to immune modulation caused by the target vectors 16  Huang: Methodology (lead); formal analysis (lead); writing-review and editing (supporting).

CONFLICTS OF INTEREST
The authors declare no conflicts of interest.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.13055.

DATA AVAILABILITY STATEMENT
Data cannot be shared publicly because of the policy by the Health and Welfare Data Center (HWDC), MOHW based on the Personal Data Protection Act (contact information for data application: https://dep.mohw.gov.tw/dos/cp-5119-59201-113.html). All databases were encrypted due to privacy concerns but linkable for research purposes and limited to use at the HWDC only.